tbuckley/cabot-search huggingface dataset:
Can I have blood tests to check everything is alright?
Authors: Lewis F Buss, David Spitzer, Jessica C Watson
Journal: BMJ (2023)

Box -"What you need to know"-Most requests for check-up blood tests are motivated by a specific health concern or symptoms -addressing these specifically may be most fruitful.-Explain the limitations of blood tests in asymptomatic people -particularly the rate of false positive results.-There are potential harms associated with over testing and these are rarely appreciated by patients.A frank discussion about when harms are likely to outweigh the benefits, and vice versa, may be helpful.
Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6
Authors: Shanshan Huang, Zhuo Xie, Jing Han, Huiling Wang, Guang Yang, Manying Li, Gaoshi Zhou, Ying Wang, Lixuan Li, Li Li, Zhirong Zeng, Jun Yu, Minhu Chen, Shenghong Zhang
Journal: Genome biology (2023)

Abstract Background Intestinal barrier dysfunction plays a central role in the pathological onset of Crohn’s disease. We identify the cadherin superfamily member protocadherin 20 (PCDH20) as a crucial factor in Crohn’s disease. Here we describe the function of PCDH20 and its mechanisms in gut homeostasis, barrier integrity, and Crohn’s disease development. Results PCDH20 mRNA and protein expression is significantly downregulated in the colonic epithelium of Crohn’s disease patients and mice with induced colitis compared with controls. In mice, intestinal-specific Pcdh20 knockout causes defects in enterocyte proliferation and differentiation, while causing morphological abnormalities. Specifically, the deletion disrupts barrier integrity by unzipping adherens junctions via β-catenin regulation and p120-catenin phosphorylation, thus aggravating colitis in DSS- and TNBS-induced colitis mouse models. Furthermore, we identify activating transcription factor 6 (ATF6), a key chaperone of endoplasmic reticulum stress, as a functional downstream effector of PCDH20. By administering a selective ATF6 activator, the impairment of intestinal barrier integrity and dysregulation of CHOP/β-catenin/p-p120-catenin pathway was reversed in Pcdh20 -ablated mice with colitis and PCDH20 -deficient colonic cell lines. Conclusions PCDH20 is an essential factor in maintaining intestinal epithelial homeostasis and barrier integrity. Specifically, PCDH20 helps to protect against colitis by tightening adherens junctions through the ATF6/CHOP/β-catenin/p-p120-catenin axis.
A novel polypeptide CAPG-171aa encoded by circCAPG plays a critical role in triple-negative breast cancer
Authors: Runjie Song, Peilan Guo, Xin Ren, Lijun Zhou, Peng Li, Nafis A Rahman, Sławomir Wołczyński, Xiru Li, Yanjun Zhang, Mei Liu, Jiali Liu, Xiangdong Li
Journal: Molecular Cancer (2023)

Abstract Background The treatment of Triple-negative breast cancer (TNBC) has always been challenging due to its heterogeneity and the absence of well-defined molecular targets. The present study aims to elucidate the role of protein-coding circRNAs in the etiology and carcinogenesis of TNBC. Methods CircRNA expression data in TNBC (GEO: GSE113230, GSE101123) were reanalyzed and then circCAPG was selected for further study. To identify the polypeptide-coding function of circCAPG, a series of experiments, such as Mass spectrometry and dual-luciferase reporter assays were conducted. Cell proliferation, apoptosis and metastasis parameters were determined to investigate the cancerous functions CAPG-171aa plays in both TNBC organoids and nude mice. Mechanistically, the relation between CAPG-171aa and STK38 in TNBC was verified by immunoprecipitation analyses and mass spectrometry. The interactions between SLU7 and its binding site on circCAPG were validated by RIP-qPCR experiments. Results In both TNBC clinical samples and cell lines, the expression level of circCAPG was identified to be higher compared with normal ones and positively correlated with the overall survival (n = 132) in a 10-year follow-up study, in which the area under the curve of receiver operating characteristic was 0.8723 with 100% specificity and 80% sensitivity. In addition, we found that circCAPG knockdown (KD) significantly inhibited the growth of TNBC organoids. Intriguingly, circCAPG can be translated into a polypeptide named CAPG-171aa which promotes tumor growh by disrupting the binding of serine/threonine kinase 38 (STK38) to SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) and thereby preventing MEKK2 ubiquitination and proteasomal degradation. Furthermore, we found that SLU7 Homolog- Splicing Factor ( SLU7 ) can regulate the bio-generation of circCAPG through binding to the flanking Alu sequences of circRNA transcripts. Conclusions circCAPG significantly enhances the proliferation and metastasis of TNBC cells by encoding a novel polypeptide CAPG-171aa and afterwards activates MEKK2-MEK1/2-ERK1/2 pathway. Additionally, the formation of circCAPG is found to be mediated by SLU7 . The present study provides innovative insight into the role of protein-coding circRNAs CAPG-171aa in TNBC, and its capacity to serve as a promising prognostic biomarker and potential therapeutic target in TNBC. Graphical abstract
Selected Articles from This Issue
Journal: Clinical Cancer Research (2023)

Highlights| July 05 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2023 American Association for Cancer Research2023American Association for Cancer Research Clin Cancer Res (2023) 29 (13): 2337. https://doi.org/10.1158/1078-0432.CCR-29-13-HI Related Content A commentary has been published: Devimistat in Combination with Gemcitabine and Cisplatin in Biliary Tract Cancer: Preclinical Evaluation and Phase Ib Multicenter Clinical Trial (BilT-04) A commentary has been published: Increased Nerve Density Adversely Affects Outcome in Oral Cancer A commentary has been published: A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer View more A commentary has been published: Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record July 5 2023 Citation Selected Articles from This Issue. Clin Cancer Res 1 July 2023; 29 (13): 2337. https://doi.org/10.1158/1078-0432.CCR-29-13-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Devimistat (CPI-613) is a novel inhibitor of key mitochondrial enzymes in the tricarboxylic acid cycle, but it failed to show an improvement in survival in pancreas cancer. Given the short half-life of devimistat, Mohan and colleagues conducted in vitro dose modeling experiments that demonstrate synergism of devimistat in combination with gemcitabine and cisplatin and, at higher doses or prolonged exposures to devimistat, a significant decrease in mitochondrial respiration. The phase Ib clinical trial supported by preclinical work evaluated higher doses at longer infusion times and demonstrates a favorable safety profile with promising initial efficacy, and it identified a recommended phase II dose currently under further investigation in a phase II randomized trial. Tumor BRAFp.V600E mutation is responsible through the activation of the MAP kinase pathway for the loss of expression of proteins involved in the iodine metabolism in thyroid cancer. Leboulleux and colleagues explored the efficacy and safety of... You do not currently have access to this content.
Diagnostic Performance and Safety of Positron Emission Tomography with 18F-rhPSMA-7.3 in Patients with Newly Diagnosed Unfavourable Intermediate- to Very-high-risk Prostate Cancer: Results from a Phase 3, Prospective, Multicentre Study (LIGHTHOUSE)
Authors: Devaki Shilpa Surasi, Matthias Eiber, Tobias Maurer, Mark A. Preston, Brian T. Helfand, David Josephson, Ashutosh K. Tewari, Diederik M. Somford, Soroush Rais-Bahrami, Bridget F. Koontz, Peter J. Bostrom, Albert Chau, Phillip Davis, David M. Schuster, Brian F. Chapin, Mohamad Allaf, Gerald Andriole, Ryan J. Avery, Norbert Avril, Helen Barker, Laurence Belkoff, Lars Budäus, Michael L. Cher, Diane Chisholm, Matthew F. Covington, Ian Cox, Michael Ferrandino, Mark T. Fleming, Dinko Franceschi, Peter Gardiner, Benjamin Gartrell, David Gauden, Ergela Hasa, Rick Hermsen, Thomas Horn, Pooya Iranpour, Heather Jacene, Isuru Jayaratna, Shreyas S. Joshi, Matthew Kay, Lale Kostakoglu, Phillip Kuo, William Lavely, Mary Lokuta, Benjamin Lowentritt, Matthew P. Miller, Jeffrey W. Nix, Kenneth Ogan, Ross Penny, Morand Piert, Andrei Purysko, Gregory Ravizzini, Daniel Saltzstein, Bital Savir-Baruch, Barry A. Siegel, Thomas Steuber, Przemyslaw Twardowski, Edward Uchio, Gary A. Ulaner, Jenna M. Wixom, Don Yoo, Katherine Zukotynski
Journal: European Urology (2023)

Radiohybrid (rh)
Clinical Characterization of Patients Diagnosed with Prostate Cancer and Undergoing Conservative Management: A PIONEER Analysis Based on Big Data
Authors: Giorgio Gandaglia, Francesco Pellegrino, Asieh Golozar, Bertrand De Meulder, Thomas Abbott, Ariel Achtman, Muhammad Imran Omar, Thamir Alshammari, Carlos Areia, Alex Asiimwe, Katharina Beyer, Anders Bjartell, Riccardo Campi, Philip Cornford, Thomas Falconer, Qi Feng, Mengchun Gong, Ronald Herrera, Nigel Hughes, Tim Hulsen, Adam Kinnaird, Lana Y.H. Lai, Gianluca Maresca, Nicolas Mottet, Marek Oja, Peter Prinsen, Christian Reich, Sebastiaan Remmers, Monique J. Roobol, Vasileios Sakalis, Sarah Seager, Emma J. Smith, Robert Snijder, Carl Steinbeisser, Nicolas H. Thurin, Ayman Hijazy, Kees van Bochove, Roderick C.N. Van den Bergh, Mieke Van Hemelrijck, Peter-Paul Willemse, Andrew E. Williams, Nazanin Zounemat Kermani, Susan Evans-Axelsson, Alberto Briganti, James N'Dow
Journal: European Urology (2023)

Conservative management is an option for prostate cancer (PCa) patients either with the objective of delaying or even avoiding curative therapy, or to wait until palliative treatment is needed. PIONEER, funded by the European Commission Innovative Medicines Initiative, aims at improving PCa care across Europe through the application of big data analytics. To describe the clinical characteristics and long-term outcomes of PCa patients on conservative management by using an international large network of real-world data. From an initial cohort of >100 000 000 adult individuals included in eight databases evaluated during a virtual study-a-thon hosted by PIONEER, we identified newly diagnosed PCa cases (n = 527 311). Among those, we selected patients who did not receive curative or palliative treatment within 6 mo from diagnosis (n = 123 146). Patient and disease characteristics were reported. The number of patients who experienced the main study outcomes was quantified for each stratum and the overall cohort. Kaplan-Meier analyses were used to estimate the distribution of time to event data. The most common comorbidities were hypertension (35–73%), obesity (9.2–54%), and type 2 diabetes (11–28%). The rate of PCa-related symptomatic progression ranged between 2.6% and 6.2%. Hospitalization (12–25%) and emergency department visits (10–14%) were common events during the 1st year of follow-up. The probability of being free from both palliative and curative treatments decreased during follow-up. Limitations include a lack of information on patients and disease characteristics and on treatment intent. Our results allow us to better understand the current landscape of patients with PCa managed with conservative treatment. PIONEER offers a unique opportunity to characterize the baseline features and outcomes of PCa patients managed conservatively using real-world data. Up to 25% of men with prostate cancer (PCa) managed conservatively experienced hospitalization and emergency department visits within the 1st year after diagnosis; 6% experienced PCa-related symptoms. The probability of receiving therapies for PCa decreased according to time elapsed after the diagnosis.
Fully automatic estimation of global left ventricular systolic function using deep learning in transoesophageal echocardiography
Authors: Erik Andreas Rye Berg, Anders Austlid Taskén, Trym Nordal, Bjørnar Grenne, Torvald Espeland, Idar Kirkeby-Garstad, Håvard Dalen, Espen Holte, Stian Stølen, Svend Aakhus, Gabriel Kiss
Journal:  (2023)

Abstract Aims To improve monitoring of cardiac function during major surgery and intensive care, we have developed a method for fully automatic estimation of mitral annular plane systolic excursion (auto-MAPSE) using deep learning in transoesophageal echocardiography (TOE). The aim of this study was a clinical validation of auto-MAPSE in patients with heart disease. Methods and results TOE recordings were collected from 185 consecutive patients without selection on image quality. Deep-learning-based auto-MAPSE was trained and optimized from 105 patient recordings. We assessed auto-MAPSE feasibility, and agreement and inter-rater reliability with manual reference in 80 patients with and without electrocardiogram (ECG) tracings. Mean processing time for auto-MAPSE was 0.3 s per cardiac cycle/view. Overall feasibility was &amp;gt;90% for manual MAPSE and ECG-enabled auto-MAPSE and 82% for ECG-disabled auto-MAPSE. Feasibility in at least two walls was ≥95% for all methods. Compared with manual reference, bias [95% limits of agreement (LoA)] was −0.5 [−4.0, 3.1] mm for ECG-enabled auto-MAPSE and −0.2 [−4.2, 3.6] mm for ECG-disabled auto-MAPSE. Intra-class correlation coefficient (ICC) for consistency was 0.90 and 0.88, respectively. Manual inter-observer bias [95% LoA] was −0.9 [−4.7, 3.0] mm, and ICC was 0.86. Conclusion Auto-MAPSE was fast and highly feasible. Inter-rater reliability between auto-MAPSE and manual reference was good. Agreement between auto-MAPSE and manual reference did not differ from manual inter-observer agreement. As the principal advantages of deep-learning-based assessment are speed and reproducibility, auto-MAPSE has the potential to improve real-time monitoring of left ventricular function. This should be investigated in relevant clinical settings.
HiCognition: a visual exploration and hypothesis testing tool for 3D genomics
Authors: Christoph C. H. Langer, Michael Mitter, Roman R. Stocsits, Daniel W. Gerlich
Journal: Genome biology (2023)

Abstract Genome browsers facilitate integrated analysis of multiple genomics datasets yet visualize only a few regions at a time and lack statistical functions for extracting meaningful information. We present HiCognition, a visual exploration and machine-learning tool based on a new genomic region set concept, enabling detection of patterns and associations between 3D chromosome conformation and collections of 1D genomics profiles of any type. By revealing how transcription and cohesion subunit isoforms contribute to chromosome conformation, we showcase how the flexible user interface and machine learning tools of HiCognition help to understand the relationship between the structure and function of the genome.
Hospital admissions linked to SARS-CoV-2 infection in children and adolescents: cohort study of 3.2 million first ascertained infections in England
Authors: Harrison Wilde, Christopher Tomlinson, Bilal A Mateen, David Selby, Hari Krishnan Kanthimathinathan, Padmanabhan Ramnarayan, Pascale Du Pre, Mae Johnson, Nazima Pathan, Arturo Gonzalez-Izquierdo, Alvina G Lai, Deepti Gurdasani, Christina Pagel, Spiros Denaxas, Sebastian Vollmer, Katherine Brown
Journal: BMJ (2023)

Abstract Objective To describe hospital admissions associated with SARS-CoV-2 infection in children and adolescents. Design Cohort study of 3.2 million first ascertained SARS-CoV-2 infections using electronic health care record data. Setting England, July 2020 to February 2022. Participants About 12 million children and adolescents (age &lt;18 years) who were resident in England. Main outcome measures Ascertainment of a first SARS-CoV-2 associated hospital admissions: due to SARS-CoV-2, with SARS-CoV-2 as a contributory factor, incidental to SARS-CoV-2 infection, and hospital acquired SARS-CoV-2. Results 3 226 535 children and adolescents had a recorded first SARS-CoV-2 infection during the observation period, and 29 230 (0.9%) infections involved a SARS-CoV-2 associated hospital admission. The median length of stay was 2 (interquartile range 1-4) days) and 1710 of 29 230 (5.9%) SARS-CoV-2 associated admissions involved paediatric critical care. 70 deaths occurred in which covid-19 or paediatric inflammatory multisystem syndrome was listed as a cause, of which 55 (78.6%) were in participants with a SARS-CoV-2 associated hospital admission. SARS-CoV-2 was the cause or a contributory factor in 21 000 of 29 230 (71.8%) participants who were admitted to hospital and only 380 (1.3%) participants acquired infection as an inpatient and 7855 (26.9%) participants were admitted with incidental SARS-CoV-2 infection. Boys, younger children (&lt;5 years), and those from ethnic minority groups or areas of high deprivation were more likely to be admitted to hospital (all P&lt;0.001). The covid-19 vaccination programme in England has identified certain conditions as representing a higher risk of admission to hospital with SARS-CoV-2: 11 085 (37.9%) of participants admitted to hospital had evidence of such a condition, and a further 4765 (16.3%) of participants admitted to hospital had a medical or developmental health condition not included in the vaccination programme’s list. Conclusions Most SARS-CoV-2 associated hospital admissions in children and adolescents in England were due to SARS-CoV-2 or SARS-CoV-2 was a contributory factor. These results should inform future public health initiatives and research.
Highlighted research articles
Journal: Blood Cancer Discovery (2023)

In This Issue| July 05 2023 Highlighted research articles Author & Article Information Online ISSN: 2643-3249 Print ISSN: 2643-3230 ©2023 American Association for Cancer Research2023American Association for Cancer Research Blood Cancer Discov (2023) 4 (4): 247. https://doi.org/10.1158/2643-3230.BCD-4-4-ITI Related Content A commentary has been published: Patient-Derived iPSCs Faithfully Represent the Genetic Diversity and Cellular Architecture of Human Acute Myeloid Leukemia A commentary has been published: A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies A commentary has been published: The Polyamine–Hypusine Circuit Controls an Oncogenic Translational Program Essential for Malignant Conversion in MYC-Driven Lymphoma Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record July 5 2023 Citation Highlighted research articles. Blood Cancer Discov 1 July 2023; 4 (4): 247. https://doi.org/10.1158/2643-3230.BCD-4-4-ITI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search IDH-mutated AML is sensitive to azacytidine combinations with venetoclax or ivosidenib. Lachowiez et al. tested triple combination of these agents, as well as oral doublet of ivodesinib with venetoclax, in a phase 1b clinical trial of 31 patients with IDH1-mutated myeloid cancers. The double as well as triple combination demonstrated durable efficacy without reaching dose-limiting toxicity, comparing favorably to historical controls. Mutant IDH1 allele clearance occurred in the majority of cases within 5 cycles of therapy. Survival benefit was higher in patients with additional mutations affecting DNA methylation. Single-cell multiomic analyses reveal complex clonal dynamics underscoring potential mechanisms of response and relapse. If safety and efficacy of these findings is reproduced in the expansion phase of the trial, these regimens could be broadly applicable to high-risk IDH-mutated patients. See article, p. 276. The polyamine-hypusine axis augments the functions of eIF5A in translation, yet the role of... You do not currently have access to this content.
Ferritin light chain promotes the reprogramming of glioma immune microenvironment and facilitates glioma progression
Authors: Hongjiang Li, Chao Yang, Yanfei Wei, Xueyuan Li, Wei Jiang, Yiran Xu, Lifeng Li, Rongqun Guo, Di Chen, Peng Gao, Haohao Zhang, Hui Qin, Zhenyu Zhang, Xianzhi Liu, Dongming Yan
Journal: Theranostics (2023)

Tumor-associated macrophages (TAMs), the most abundant non-tumor cell population in the glioma microenvironment, play a crucial role in immune evasion and immunotherapy resistance of glioblastoma (GBM). However, the regulatory mechanism of the immunosuppressive TME of GBM remains unclear.
Tsp-1<sup>+</sup> microglia attenuate retinal neovascularization by maintaining the expression of Smad3 in endothelial cells through exosomes with decreased miR-27a-5p
Authors: Qian Luo, Zihua Jiang, Jingyi Jiang, Linxi Wan, Yan Li, Yuke Huang, Jin Qiu, Keming Yu, Jing Zhuang
Journal: Theranostics (2023)

Rationale: Microglia with a repertoire of functions are critical in pathological regulation of angiogenesis in the retina.However, retinal microglia with beneficial contributions and corresponding mechanisms during pathological neovascularization are poorly understood.Methods: We conducted a bioinformatic comparison of public single-cell RNA transcriptome data between retinal microglia from mice with oxygen-induced retinopathy (OIR) and an antiangiogenic microglial population named MG3 from the spine.The essential beneficial factor thrombospondin-1 (Tsp-1) from microglia was discovered and then validated in the retina of mice with OIR at P17. Exosomes were isolated from Tsp-1-knockout microglia (KO-Exos) and Tsp-1 + microglia (NT-Exos).Human umbilical vein endothelial cells (HUVEC) morphology studies, exosomes' miRNA sequencing, luciferase reporter assay, miRNA loss of function studies, and intravitreal injection were used to explore the mechanism of Tsp-1 and microglia-associated retinal angiogenesis. Results:The bioinformatic analyses of single-cell RNA-seq data indicated that a subtype of retinal microglia named RMG1 shares features with MG3 in regulating wound healing, cell adhesion, and angiogenesis.Remarkably, Tsp-1, an extracellular matrix protein with robust inhibition of angiogenesis, was especially expressed in both MG3 and RMG1.However, the scarcity of Tsp-1 + cells was observed in RMG1, which could be an obstacle to attenuating retinal neovascularization.Subsequently, we found that exosomes derived from Tsp-1 + microglia inhibit the migration and tube formation of HUVEC.Moreover, the knockout of Tsp-1 led to the enrichment of miR-27a-5p in exosomes from microglia and promoted angiogenesis compared to that of NT-Exos in vitro.Furthermore, in the luciferase reporter assay on the transcriptional activity of the promoter, we demonstrated that Tsp-1 negatively regulates miR-27a-5p expression.In addition, SMAD family member 3 (Smad3), a receptor-activated Smad protein that is conducive to vascular homeostasis, was defined as a functional target gene of miR-27a-5p.These data were consistently confirmed in vivo in the retina of mice with OIR.Conclusion: Collectively, the Tsp-1/miR-27a-5p/Smad3 axis is involved in microglia-related and exosome-mediated antiangiogenic regulation of the retina.Therefore, this study reveals a novel mechanism by which retinal microglia maintain vascular homeostasis, thereby providing a new therapeutic target for pathological neovascularization.